The currently related art involves various diverging physiological theories. Firstly, in Stress Theory, the term “stress” is defined as follows: “1. The reaction of the animal body to forces of a deleterious nature, infections and various abnormal states that tend to disturb its normal physiologic equilibrium (homeostasis). 2. The resisting force set up in a body as a result of an externally applied force.”
Secondly, in Disorder Theory, the term disorder is involved in the basic law of the universe. Living creatures are ordered forms that employ combinations of information systems, chemical reactions, and mechanical mechanisms to acquire energy from their environment in order to maintain their structural integrity and function as well as to replicate. To be alive is to be unceasingly stressed by the demands of energy acquisition and structural maintenance.
Thirdly, Occam's Razor, a key theory or concept in scientific philosophy, suggests that the best approach to a complex problem is to assume that the simplest explanation, or set of explanations, is correct until proven otherwise.
That humans and animals are equipped with physiological mechanisms that enable them to resist and repair the damaging effects of stressful stimulus, including coagulation, inflammation, scab formation, wound repair, and tissue maintenance, has been long understood. The observed reactions to stress are numerous, confusing, and interrelated; and thusfar, no attempt has been made to describe a single mechanism in the related art that can explain these various phenomena.
The Stress Theory may provide fresh insights to the nature of embryology, neonatology, physiology, immunology, pharmacology, and pathology. The Stress Theory may offer improved understanding of the mechanisms of drug actions, systemic vascular resistance, blood flow and distribution, blood pressure, atherosclerosis, thromboembolism, capillary homeostasis, apoptosis, embryological tissue development, muscle hypertrophy, athletic cardiovascular “conditioning”, blood coagulation, tissue inflammation, wound healing, Virchow's Triad, the “Fight or Flight” stress syndrome of Hans Seyle, Surgical stress, tissue remodeling and maintenance, as well as numerous manifestations of pathology by describing all these in terms of the effects of a cohesive stress-opposing mechanism that operates continuously to maintain homeostasis and tissue integrity in the animal body.
Stress Theory is predicated on the alternate hypothesis that coagulation Factors VII and VIII are blood-borne stress agents that respectively cause local and systemic elevations of thrombin levels and synergize each other's actions to produce hyper-elevations of thrombin at the site of stress (injury) and that thrombin is responsible for the numerous symptoms and effects exerted by the stress mechanism. Stress Theory offers a simpler and more complete explanation of hemostasis and coagulation than presently prevailing Cascade Theory, plus a simple explanation of wound healing, tissue maintenance, and important aspects of embryological development that is presently lacking.
Stress Theory assigns a role to Factor VII that might be compared to the “Extrinsic” cascade. Factor VII circulates in flowing blood and is separated from exposure to the underlying collagen that constitutes the major component of blood vessel structure by the vascular endothelium, which is only one-cell-layer in thickness. Disruption of the vascular endothelium, therefore, exposes Factor VII to collagen, thereby causing its activation, which is normally localized and focused the effects of the Stress Mechanism at the site of injury (stress).
Likewise, the role of Factor VIII loosely corresponds to the “Intrinsic” cascade. Factor VIII is a hormone that is produced and is released directly into the blood by the vascular endothelium, a gland, under the control of the Sympathetic Nervous System (SNS), so that its level varies with the tone and activity levels of the SNS. Factor VIII's activity is systemic and its function is to regulate the activity level of the Stress Mechanism.
Both Factors VII and Factor VIII activate thrombin, and their combined effects cause localized hyper-elevations of thrombin that focus the effects of the stress mechanism at the site of stress and injury. The role of thrombin, thus, corresponds to the “Final Common Pathway” as described by Cascade Theory.
Stress Theory hypothesizes that thrombin is the primary enzymatic effecter agent of the stress mechanism. Thrombin is the known cause of numerous effects, including platelet activation, cell mitosis, cell hypertrophy, increased cell metabolism, inflammation, collagen production, and the conversion of fibrinogen to insoluble fibrin. Thrombin is closely associated with embryological development, wound healing, coagulation, malignancy, and tissue maintenance. Stress Theory hypothesizes that thrombin produces these multiple effects via a common mechanism that has yet to be identified in the related art.
Stress Theory postulates two mechanisms of hemostasis, both of which are controlled by blood levels of thrombin and “insoluble” fibrin. These mechanisms are: 1) Capillary Hemostasis, which is initiated by closure of a molecular level Capillary Gate Mechanism governed by varying levels of “insoluble” fibrin and 2) Systemic Hemostasis, which is manifested by the familiar blood clot formation process that occurs in larger vessels. Hemostasis is initiated by declines in blood turbulence and mixing, which, in turn, is initiated by increased blood levels of “insoluble” fibrin, a three-dimensional molecule with physical properties absent in its precursor, “soft” fibrin, and is enhanced by the formation of fibrin strands that connect various blood components to one another as turbulence and mixing decline.
The Stress Theory implies that changes in systemic vascular resistance occur in accord with the operation of the Capillary Gate Mechanism and the degree of capillary hemostasis as opposed to muscular contraction or relaxation of larger blood vessels. The Stress Theory asserts that the rapidly reversible physical properties of the three-dimensional matrix structure of insoluble fibrin, as controlled and facilitated by varying levels of Factor VIII, enable the opening and closing of the hypothesized Capillary Gate Mechanism to produce capillary hemostasis and indirectly regulate capillary perfusion. Simultaneously, insoluble fibrin increases systemic blood viscosity, which reduces blood turbulence and mixing, thereby increasing blood coagulability and thereby inducing clot formation. Hyper-elevations of insoluble fibrin in the immediate vicinity of stressful stimulus (injury), determined by the combined effects of Factors VII and VIII, reduce turbulence and mixing below a critical threshold, whereupon fibrin strands form inter-connections among blood components that further reduce turbulence and mixing, and clot formation proceeds to completion.
Chronic systemic elevations in blood viscosity, caused by persistent stressful stimulus and other factors, in turn, cause reductions in blood turbulence and mixing that accelerate atherosclerosis in the arterial tree and increase the risk of thromboembolism in the venous system. Systemic vascular resistance and blood pressure vary directly and cardiac output and tissue perfusion vary inversely, with the degree of closure of the Capillary Gate Mechanism as determined by the level of stress, SNS activation, and Factor VIII release.
Although thrombin plays an essential role in coagulation, most thrombin generation occurs after clot formation, suggesting that it may have additional functions. Stress Theory postulates that thrombin initiates coagulation and inflammation as a prelude to wound healing as well as attracts various wound-healing cell types to the site of injury. Thrombin subsequently induces fibroblast mitosis, metabolism, proliferation, and collagen production as an integral part of the wound healing process. Thrombin levels continue to be elevated at the site of stress to regulate the wound-healing process in accord with continued collagen exposure to flowing blood. Thereby maintaining Factor VII activation when wound healing is substantially complete and collagen is sealed from exposure to flowing blood, thrombin levels fall. The decline in thrombin levels induces fibroblast apoptosis, thereby signaling an end to the “active phase” of wound healing. Maintenance levels of thrombin may stimulate collagen replenishment and tissue maintenance and remodeling, as evidenced by skin necrosis, ulceration, and disturbances of wound repair that sometimes result from treatment with coumadin, wherein coumadin exerts anti-thrombin effects.
Growing evidence suggests that the embryological development of complex multi-celled eukaryotic organisms may be largely governed by genetic programming contained in “junk” DNA in the form of “introns” that, in the case of humans, constitutes 95 percent or more of the genome. The introns may exert their effects on embryological development by controlling the timing of developmental processes, such as stem cell maintenance, cell proliferation, and apoptosis. Thrombin has been shown to be closely associated with cell maintenance, metabolism, hypertrophy, proliferation, angiogenesis and apoptosis. Thrombin appears to play an important role in embryological development, as evidenced by fetal developmental defects that are associated with the administration of thrombin inhibitors to pregnant females and studies that demonstrate the role of thrombin in embryological development. Thus, the present hypothesis considers that introns control embryological development by controlling localized thrombin levels at precise time intervals. The Stress Mechanism, which also governs thrombin levels, may play a complimentary and synergistic role in embryological development by stimulating newly-developed organs and tissues to grow and enlarge in response to the stresses associated with fetal development. Assuming the presence of thrombin-sensitive growth and mitosis receptors common to all cells, the combined effects of introns and the stress mechanism to regulate thrombin levels may provide a simplified model of embryological development in complex organisms.
Nearly all forms of disease cause activation of the Stress Mechanism, typically manifested by a triad of factors: (1) elevated blood levels of Factor VIII, (2) increased blood viscosity, and (3) increased blood coagulability. These factors are often accompanied by a wide variety of seemingly unrelated pathological symptoms due to inflammation, fibrin generation, and fibroblast proliferation. The Stress Mechanism may account for these symptoms. The Stress Mechanism is powerful, and may cause pathological effects, including malignancy, that are at odds with its healing function. The cause of these symptoms has not yet been fully understood in the related art. As such, stress-related diseases, such as rheumatoid disease, the tissue damage of diabetes, ARDS, asthma, inflammatory bowel disease, malignancy, eclampsia, and DIC remain misunderstood. As such, the condition in relation to the manner in which stress-related conditions appears to exacerbate the incidence and severity of one another, e.g. in diabetes, pregnancy, or CREST syndrome also remains misunderstood the related art, the fact that patients afflicted with one form of cancer are at increased risk of additional forms of cancer, the manner in which conditions that activate the stress mechanism may increase the risk of atherosclerosis and malignancy and the manner in which environmental factors may increase the risk of stress-related disease also remain problematic in the related art. The associations between hypertension, systemic vascular resistance, blood viscosity, blood coagulability, atherosclerosis, and heart disease remain a mystery in the related art, whereby new forms of treatment and research are stymied. Finally, logical ways to employ anesthesia and surgical techniques to control stress and improve surgical outcome have yet to be seen in the related art.
The Stress Theory is based on a set of inter-related, testable hypotheses, related to further factors.
A Stress Mechanism is present in all vertebrate species that involves the activities of Factors VII, Factor VIII, and thrombin. The Stress Mechanism operates continuously to control coagulation, scab formation, wound healing, and tissue maintenance. “Stress” is defined as any stimulus that causes activation of the Stress Mechanism.
A sub-microscopic, molecular-level Capillary Gate Mechanism exists that is controlled by the effects of Factors VII and VIII and is an integral component of the Stress Mechanism. The Capillary Gate Mechanism regulates capillary hemostasis. The degree of capillary hemostasis, i.e., closure of the Capillary Gate Mechanism, indirectly affects capillary bed perfusion, systemic vascular resistance, blood pressure, and cardiac output.
Factor VIII is a systemic stress hormone that is continuously released into the bloodstream by a gland called the vascular endothelium which is under the direct control of the Sympathetic Nervous System (SNS) in accordance with constantly varying levels of stressful stimulus. The function of Factor VIII is to control the activity level of the Stress Mechanism. Factor VIII comprises the following components: Factor VIIIC and Von Willebrand's Factor (VWF). The VIIIC component causes the systemic conversion of prothrombin to thrombin and the activation of Factor XIII, whereby fibronectin cross-links are added to developing fibrin strands to form a three-dimensional “insoluble” fibrin molecule. The VWF component stabilizes, enhances, and prolongs the function of the VIIIC component, thereby indirectly affecting thrombin activity. The VWF molecule also serves as a molecular component of the Capillary Gate Mechanism.
Factor VII is a companion stress agent that is activated by exposure to collagen. The actions of Factor VII occur at the site of tissue disruption. Like Factor VIII, Factor VII catalyzes the conversion of prothrombin to thrombin and thereby synergizing the effects of Factor VIII to produce localized hyper-elevations of thrombin, and thereby focusing the effects of the Stress Mechanism on the site of stress (injury).
Elevated blood levels of thrombin cause elevated blood levels of insoluble fibrin. Insoluble fibrin simultaneously causes both closure of the Capillary Gate Mechanism and elevations in blood viscosity. Increased blood viscosity causes “damping” (decrease) in blood turbulence and mixing. Thrombin also stimulates the activation of fibroblasts and other cell types to control embryonic organ development, wound healing, and tissue maintenance.
Turbulence and mixing induced by pulsatile blood flow, inhibits both atherosclerosis and coagulation. Coagulation occurs spontaneously when turbulence and mixing fall below a critical threshold. Atherosclerosis is accelerated by chronically lowered levels of turbulence and mixing in the blood.
Under ordinary circumstances, coagulation occurs only in the presence of the combined effects of Factors VII and VIII. The combined effects are synergized so as to induce hyper-elevations of thrombin at the site of injury that lowers turbulence and mixing below the threshold of clot formation.
The VIIIC component of Factor VIII is so unstable that it is completely inactive in the absence of VWF. Variations in the quality and/or quantity of VWF, therefore, cause variations in both the half-life and activity levels of Factor VIII. This circumstance explains the various coagulation-enhancing effects of VWF and the manner in which increased levels of stress cause the half-life of Factor VIII to be prolonged, regardless of subsequent lowering of SNS activity levels.
The other effects of thrombin, including inflammation, cell proliferation, collagen production, and increased cell metabolism, are regulated by the Stress Mechanism in the same manner as coagulation so as to govern the wound-healing process, key aspects of embryological development, and tissue remodeling and maintenance.
Factor VIII is released in response to pure psychic stress, thereby causing pre-emptive elevations in blood coagulability and capillary hemostasis and thereby minimizing blood loss in the event of subsequent injury. Further, Factor VIII functions as an integral part of the “fight or flight” stress phenomenon described by Hans Selye.
The hitherto mysterious pathological effects associated with Surgical Stress and the Stress Syndrome, including dementia, stroke, myocardial infarction, bowel ileus, vasomotor instability, and sudden death, are primarily explained by widespread and prolonged stress-induced closure of the Capillary Gate Mechanism that results in tissue oxygen starvation and damage in affected capillary beds. This will be called “Capillary Fibrin Stress” (CFS). Microvascular disturbances in nervous tissue may offer an example of CFS.
Apoptosis is caused by a sudden decline of thrombin levels below a critical threshold required to sustain fibroblast metabolism and mitosis. This circumstance normally signifies the completion of the active phase of wound healing and plays a critical role in embryological development.
Malignancy is an aberration of the wound-healing process in which prolonged and excessive levels of stressful stimulus and hyper-elevated thrombin levels cause the invasion of normal tissues by thrombin-activated fibroblasts; thereby resulting in a self-sustaining release of thrombin that inhibits apoptosis.
SNS activity levels are stimulated by semi-independent pathways for psychic stress, i.e., conscious awareness of pain and danger, and somatic stress, i.e., physical tissue disruption. The simultaneous control of both psychic and somatic stress is necessary to produce synergistic reductions in SNS and Stress Mechanism activity levels that may prevent CFS, systemic inflammation, hypercoagulability, and other pathological effects of stressful stimuli and Surgical Stress.
The various elements of the Stress Theory will be discussed in detail. Clinical examples, including eclampsia, essential hypertension, diabetes, DIC, and ARDS will be offered as illustrations of the role that stress may play in disease. FIG. 1 (related art) shows a diagram providing an outline of the proposed Stress Mechanism.
Recent advances in the understanding of the characteristics of Factor VIII may offer fresh insight as to the presence and nature of a fast-acting, sub-microscopic, molecular-level Capillary Gate Mechanism. A mechanism that regulates blood flow and hemostasis at the capillary level has long been suspected, but never identified. The Capillary Gate Mechanism hypothesis is attractive because it offers an explanation of observed capillary hemostasis. Capillaries lack musculature and cannot contract, so capillary vasoconstriction is impossible. However, capillaries and vascular endothelium have been shown to be innervated with both sympathetic and parasympathetic nerve endings that may govern the release of Factor VIII and other vasoactive substances. Theories of capillary endothelial cell swelling that occlude the capillary lumen have been proposed in the related art, but are not supported by any evidence. Theories of pre-capillary sphincter contraction that might explain capillary hemostasis are likewise lacking in substance, because pre-capillary sphincters and vessels invariably relax after short periods of contraction and subsequently exhibit compensatory vasodilation.
The Capillary Gate Mechanism hypothesis also offers an improved explanation for the regulation of blood flow as well as distribution and systemic vascular resistance. The surface area of the capillaries is many times greater than that of all larger vessels combined; and the hemodynamic pressures and flows are vastly lower so that control of blood flow might be more easily explained at the capillary level than at the level of larger blood vessels. The Capillary Gate Mechanism hypothesis might also offer an improved explanation of the Blood Brain barrier and cerebral autoregulation.
Witte et al. have demonstrated microvascular endothelial receptor sites for fibrinogen, fibronectin, and Factor VIII, suggesting that these are structural elements of the Capillary Gate Mechanism. Since insoluble fibrin contains fibronectin, the present invention considers that fibronectin receptor sites may actually serve as attachment sites for insoluble fibrin. The invention considers that the Capillary Gate Mechanism is regulated by the blood level of Factor VIII, as determined by the activity level of the Sympathetic Nervous System. Rising levels of Factor VIII cause increased blood levels of thrombin, which cause elevated levels of insoluble fibrin, whereupon both Factor VIII and insoluble fibrin act in concert with fibrinogen to obstruct capillary flow and close the Capillary Gate.
Thrombin has been demonstrated to inhibit the conversion of plasminogen to plasmin, and insoluble fibrin contains plasminogen that is an integral part of its structure. The present invention considers that when levels of Factor VIII decline, the resulting decrease in thrombin level allows spontaneous conversion of plasminogen to plasmin, which attacks and dismembers the insoluble fibrin molecule into “fibrin split products.” In addition, enzymes such as urokinase and Tissue Plasminogen Activator (TPa) may attack insoluble fibrin and prevent closure of the capillary gate in certain tissues where uninterrupted capillary perfusion is vital, such as brain and heart tissue. This circumstance might explain the “blood/brain barrier” and cerebral autoregulation.
In addition, the observations of Holemans et al. that vasoactive drugs are associated with elevated rates of fibrin turnover and that “vasodilators” are associated with greater levels of fibrin turnover than “vasopressors” is consistent with the foregoing concept. The present invention considers that vasopressors enhance fibrin formation and the closure of the Capillary Gate, while vasodilators enhance the breakdown of fibrin and the opening of the Capillary Gate. These agents may effect changes in systemic vascular resistance and, therefore, blood pressure by manipulating the operation of the Capillary Gate.
Angiodysplasia, an age-related bleeding diathesis in which visible damage to capillaries occurs, may offer direct evidence of a Capillary Gate Mechanism. Angiodysplasia has been shown in all studied forms to be associated with damaged or absent VWF, and it occurs in von Willebrand's Disease. Angiodysplasia also occurs in uremia, aortic stenosis, and Idiopathic Hypertrophic Subaortic Stenosis, all of which have been shown to be associated with functional abnormalities of the VWF molecule. In the absence of adequate levels of functioning VWF, the half-life of the VIIIC component of the Factor VIII complex becomes undetectable. As such, severe defects in the quality or quantity of VWF results in complete cessation of all aspects of Factor VIII complex activity. In contrast, angiodysplasia does not occur in classical hemophilia, wherein only VIIIC is absent and normal levels of VWF are present. This circumstance suggests that the VWF portion of the Factor VIII complex plays a dominant role in Capillary Gate function compared to the VIIIC component, and it defects in the quality or quantity of VWF which causes a structural defect in the Capillary Gate Mechanism so severe as to result in visible capillary damage known as angiodysplasia.
Fibrin “cuffs” and deposits have been noted at the entrance and in the lumen of capillaries in association with venous obstruction. Fibrin deposits in blood vessels and tissues and hyper-elevations of blood coagulability are consistently observed in association with severe stress states. These observations are consistent with hyper-elevations of blood fibrin levels that commonly occur in states of stress. The present invention considers the hypothesis that severe stress may cause overproduction of insoluble fibrin that normally functions to close the Capillary Gate Mechanism and regulate blood coagulability, with the result that excess fibrin accumulates at the entrance of the capillary gate and deposits on vessel walls, as in DIC.
Sielenkamper et al. have demonstrated the existence of unexplained increases in bowel capillary flow in association with epidural anesthesia, despite lowered systemic blood pressure. Kabon et al. have demonstrated increased tissue oxygenation associated with epidural anesthesia, again despite lowered systemic blood pressure. Kapral et al. have demonstrated higher pH in bowel tissue associated with epidural anesthesia. Epidural anesthesia has been associated with reduced thrombophlebitis, reduced blood loss, increased stroke volume, decreased systemic vascular resistance, and overall decrease in morbidity as well as mortality in high risk patients. These studies are consistent with the hypothesis that epidural anesthesia may interfere with the systemic release of Factor VIII by decreasing SNS tone and activity levels, thereby reducing blood levels of insoluble fibrin, thereby preventing closure of the Capillary Gate, and thereby improving capillary bed perfusion.
Sielenkamper et al. have also demonstrated unexplained decreases in bowel capillary flow in association with sepsis, a powerful cause of stress. Sepsis is known to cause stressful effects and elevations in blood levels of Factor VIII. The observed decreases in capillary flow may be explained by closure of the Capillary Gate caused by sepsis-induced elevated levels of Factor VIII.
Luostarinen et al. demonstrated unexplained injury-induced decreases in adjacent (uninjured) bowel capillary flow that was restored by direct application of lidocaine. The decreases in capillary flow may be explained by the activities of Factors VII and VIII in the vicinity of injury. The present invention considers that the direct application of lidocaine to capillary beds may block the function of exposed SNS nerve endings that terminate in the capillary endothelium, thereby preventing the release of Factor VIII, and thereby opening the Capillary Gate and restoring of capillary flow.
Weinberg et al. have demonstrated that bupivacaine inhibits the accumulation of acidic products of anaerobic glycolysis during ventricular fibrillation (VF) in dogs, whereas tissue oxygen levels are not affected. However, Weinberg et al. could not explain this result. Like lidocaine, intravenous dosage with bupivacaine may interrupt the function of exposed nerve endings in the vascular endothelium, thereby inhibiting the release of Factor VIII and preventing the closure of the Capillary Gate Mechanism. This condition might promote capillary perfusion or diffusion during VF, thereby mitigating the accumulation of acidic metabolic products in cardiac tissue during VF. Oxygen levels would be expected to be depleted rapidly regardless of the effects of bupivacaine, VF would interrupt the transport of oxygen via systemic circulation. Thereby causing cardiac tissue to rapidly deplete oxygen stores and revert to anaerobic glycosis metabolism, which, in turn exacerbates the production of acidic metabolic products.
Anaphylactic shock may also provide insights to Capillary Gate structure and function. Anaphylactic shock differs from other forms of shock in that it is not associated with elevated fibrin levels or decreased cardiac output, but is characterized by severe hypotension, hives, and angioneurotic edema that may cause swelling of airway tissues so severe as to result in death. Anaphylactic shock is associated with repeated exposure to antigenic drugs and chemicals, notably protamine and bee venom, but can be successfully treated with epinephrine, which a compound causes the release of Factor VIII and enhances the conversion of fibrinogen to insoluble fibrin. The present invention considers that the cause of anaphylaxis symptoms may be a sudden, widespread failure of the Capillary Gate Mechanism that causes a severe translocation of red cells and plasma from large blood vessels to capillaries and extravascular space. Such a phenomenon might occur if the immune system were to attack one of the Capillary Gate components in association with exposure to antigen, thereby causing sudden, widespread failure of the Capillary Gate mechanism. Existing studies suggest that anaphylaxis may involve sudden a complement-mediated attack on the VWF molecule followed by activation of plasminogen, thereby causing widespread destruction of the insoluble fibrin molecule as thrombin levels fall in response to the inactivation of VWF. These studies are consistent with the hypothesis that insoluble fibrin and VWF are important structural components of an existing Capillary Gate Mechanism. FIG. 2 (related art) shows a diagram of the mechanism of the Capillary Gate.
Serine protease thrombin is a powerful, multifunctional and ubiquitous stress enzyme that plays a central role in coagulation, DIC, injury, inflammation, blood vessel repair, and tissue remodeling.
Thrombin mediates embryological cell proliferation and tissue development, as evidenced by serious birth defects that occur with fetal exposure to anti-thrombin medications, and it inhibits apoptosis. Declines in thrombin levels may, therefore, explain the apoptosis that plays an important role in both embryological development and wound healing.
Thrombin is routinely employed in the operating theatre to control bleeding from cut surfaces because it mediates platelet activation and fibrin deposition. Thrombin also stimulates fibroblast metabolism, proliferation, hypertrophy, and collagen production as an integral part of wound healing. However, Thrombin supports and promotes malignancy. Thrombin may activate leukocytes, polymorphonucleocytes, monocytes, macrophages and endothelial cells as part of the inflammatory process and stimulates angiogenesis. Thrombin has been associated with abnormal proliferation of vascular smooth muscle cells and pathogenic vascular remodeling. Chronic hypoxia, chemical exposure, and other forms of stress, may induce thrombin-mediated pathological forms of tissue proliferation. Thrombin may mediate cellular hypertrophy and tissue hypertrophy such as muscular hypertrophy, that occur with mechanical stress to muscles. Thrombin's mitogenic effects appear to be inhibited by glucocorticoids. Thereby explaining certain therapeutic effects of these agents.
Thrombin generation appears to depend on the presence of calcium and Factors VIII and IX. During the coagulation process, thrombin enzymatically cleaves fibrinogen into fibrin “monomers” that polymerize into strands (“soft” fibrin). Thrombin simultaneously catalyzes the activation of Factor XIII (“fibrin stabilizing factor”), which forms fibronectin cross-links in the developing fibrin structure so as to produce a three-dimensional fibrin “matrix” structure known as “insoluble” fibrin. Thrombin directly induces platelet activation and platelet elaboration of thromboxane, thereby causing vasoconstriction and reduced blood flow in the immediate vicinity of activated platelets.
Thus, a long-felt need is seen to exist for a unified theory that endeavors to explain the biological reaction to stressful stimuli in terms of a simple, physiologic mechanism. Furthermore, a long-felt need is seen to exist for therapies and compositions which utilize unified principles of stress, coagulation, inflammation, wound healing, embryological development, and tissue maintenance.